Traumatic Brain Injury (TBI) is a frequent combat injury. Unfortunately, survivors of head trauma may go on later to develop recurrent seizures. This problem, termed post-traumatic epilepsy, is associated with significant morbidity and mortality. The most common form of post-traumatic epilepsy originates in the hippocampus of the temporal lobe. Up to one third of such patients have medically intractable post- traumatic epilepsy. As such they are at risk for a number of complications including sudden death, physical injuries, memory loss and a host of psychosocial issues. Due to this problem, a call has been made by the American Epilepsy Society for chronic studies of post-traumatic epilepsy. Therefore, we have tailored our proposal to provide information for this need. In our preliminary studies, we have used a model of TBI called controlled cortical impact (CCI) in adult male rats and found that seizure threshold is not only decreased after CCI, but continues to decline for at least 6 months thereafter. At this time we propose to evaluate seizure threshold chronically after lateral CCI over the life-span of the adult rat, which is about 24 months. During that time, we plan to perform electrophysiological, histological and biochemical experiments in vitro and in vivo techniques to evaluate seizure threshold in hippocampal subregions, including the dentate, CA3 and CA1 every 6 months after CCI. We have also found in our preliminary studies, evidence that treatment with the Bcl-220-34 peptide may prevent the lowering of seizure threshold after CCI. Therefore, we will also evaluate this treatment strategy in our proposal. In addition, we will examine a potential mechanism of action for the Bcl-220-34 peptide, which may indicate mitochondrial involvement in the generation of lowered seizure threshold after TBI. To this end, we will also evaluate mitochondrial structure and function after CCI with and without treatment with the Bcl-220-34 peptide. PUBLIC HEALTH RELEVANCE: This proposal will examine a frequent complication of Traumatic Brain Injury (TBI), that being an increase in brain cell susceptibility to injury that occurs in persons surviving TBI. We will also examine a potential treatment to help prevent the occurrence of increased susceptibility to post traumatic seizures and thereby improve Veterans' healthcare.